The asymmetric construction of a stereogenic carbon center with a quaternary carbon atom remains one of the most challenging and demanding topics in the synthesis of natural products and chiral drugs. The development of efficient asymmetric methods to access complex molecules with multiple stereogenic centers also continues to be a substantial challenge in both academic research and industrial applications.
One approach toward these challenges is the use of catalytic enantioselective cascade reactions, which have emerged as powerful tools to give a rapid increase in molecular complexity from simple and readily available starting materials, thus producing enantioenriched complex compounds in a single operation. Of the developed strategies for asymmetric tandem reactions, organocatalysis provided an efficient protocol. The syntheses of substituted cyclohexenes by applying a three-component domino reaction (Enders, D, et al., Nature (2006) 441, 861; Enders, D, et al., Angew. Chem. Int. Ed. (2007) 46, 467) and by a two-component multistep Michael-nitroaldol (Henry) sequence using pentane-1,5-dial and 2-substituted nitroalkenes (Hayashi, Y, et al, Angew. Chem. Int. Ed. (2007) 46, 4922) have been described.
Although several other elegant organocatalytic tandem reactions have also been reported recently, the development of new methods for the generation of molecules with multiple stereogenic carbons, including quaternary centers, in a cascade manner remains a big challenge at the forefront of synthetic chemistry. The Michael addition reaction, being one of the most general and versatile methods for formation of C—C bonds in organic synthesis, has received much attention in the development of enantioselective catalytic protocols. Domino Michael-Michael (also called “double Michael”) reactions have been explored and demonstrated as a powerful tool in organic synthesis (for a review on double Michael reactions, see: Ihara, M, & Fukumoto, K, Angew. Chem. Int. Ed. (1993) 32, 1010). Efficient asymmetric double Michael processes have been achieved by relying on the use of chiral auxiliaries and chiral precursors for stereocontrol. However, the development of organocatalytic enantioselective versions of the reactions proved to be a challenging task, and there have been very few reports regarding the formation of quaternary and tertiary stereocenters with both excellent enantioselectivity and diastereoselectivity using α,β-unsaturated esters as Michael acceptors.
The nitroaldol reaction, also termed Henry reaction, also represents a powerful C—C bond forming tool, and the resulting nitro alcohol products can be transformed into a number of nitrogen and oxygen containing derivatives such as nitroalkenes, amino alcohols and amino acids (Palomo, C, et al., Eur. J. Org. Chem. (2007) 2561). In addition to substrate-controlled Henry reactions, organocatalytic systems that provide good stereoselectivity have been developed in recent years.
It is an object of the present invention to provide a further process that can be used to form organic molecules with multiple stereogenic carbon atoms, in particular quarternary carbon centers.